Chemotherapy May Obviate Irradiation in Ependymoma

NOTTINGHAM, England, July 23 -- In many young children with intracranial ependymoma, primary chemotherapy can delay or avoid radiotherapy without compromising survival, according to investigators here.

In 80 patients with nonmetastatic disease, the five-year rate of freedom from radiotherapy was 42%, Richard G. Grundy, M.B., ChB, of the University of Nottingham, and colleagues, reported online in The Lancet Oncology. Of 59 patients who progressed, 47 relapsed solely from loss of local control.

"These results suggest, therefore, that primary chemotherapy strategies have an important role in the treatment of very young children with intracranial ependymoma," concluded Dr. Grundy and colleagues.

More than half of children who develop intracranial ependymomas are younger than five years, making the avoidance of damage to the developing brain an important consideration in treatment planning, the authors noted. Radiation therapy offers effective treatment but also poses a risk to an immature central nervous system.

Because of this, the United Kingdom Children's Cancer Study Group/International Society of Pediatric Oncology organized a prospective study to evaluate primary chemotherapy for ependymoma in children younger than three years.

The trial arose from a previous study of primary chemotherapy for young children with any type of malignant brain tumor. In the current trial, patients three or younger at diagnosis were given alternating courses of myelosuppressive and nonmyelosuppressive chemotherapy. Radiation therapy was withheld until disease progression or relapse documented by imaging.

Chemotherapy consisted of four courses of therapy, repeated every 56 days.

• Course 1: caboplatin plus vincristine
• Course 2: methotrexate and vincristine
• Course 3: cyclophosphamide plus prehydration and mesna
• Course 4: cisplatin

For patients with localized, nonmetastatic tumors, the total radiation dose was 50 Gy administered in 25 fractions to the macroscopic tumor plus 2 cm margin. Whole neuroaxis radiotherapy was recommended for metastatic disease and consisted of 20 to 35 Gy (depending on patient age), followed by a 20-Gy boost to the tumor.

Dr. Grundy and colleagues reported findings from 89 patients, 80 of whom had nonmetastatic disease. Complete resection of the primary tumor was performed in 44 patients, subtotal resection in 41, and biopsy-only in three. One patient died perioperatively. Chemotherapy began a median of 23 days after surgery.

Subsequently, 50 patients with nonmetastatic disease progressed, and 34 underwent radiation therapy. All nine patients with metastatic disease progressed, and six of nine had radiation therapy.

The entire cohort of 89 patients a cumulative radiotherapy rate of 44.6% at three years and 49% at five years. The median time from surgery to radiotherapy was 20.3 months, and the median patient age at irradiation was 3.6 years.

Overall, 59 patients progressed, 37 of whom died. Among the 40 patients who received radiotherapy, 23 also had additional surgery. Median time to progression in the 59 patients was 1.6 years.

The three-year event-free survival for all 89 patients was 42.7%, and five-year event-free survival was 37.5%. Of 51 patients still alive at last follow-up, median follow-up was six years. Overall survival was 76.8% at three years and 60.0% at five years. Patients with nonmetastatic disease at diagnosis had slightly better survival of 79.3% at three years and 63.4% at five years.

The chemotherapy dose intensity influenced survival. Approximately equal numbers of patients had a relative dose intensity of less than 0.78, the median relative dose intensity of 0.87, and more than 0.93. Three-year postchemotherapy survival was 52.1% in patients who achieved the lowest relative dose intensity, 64% in those who achieved the median RDI, and 90.7% for patients who had the highest relative dose intensity.

Neuropsychological assessment was not incorporated into the study, which began in 1992, an era when longitudinal follow-up was not considered crucial, the investigators noted. However, an earlier single-center study that employed a similar treatment protocol included IQ assessment at diagnosis and 75 months after diagnosis. Children in that study had overall, verbal, and performance IQ scores within the normal range.